Monday, May 12, 2025
5/12/2025
Targeting T cell Subsets in Autoimmune Disease - The power of translational investigation has been exemplified by the Massachusetts General Hospital (MGH) Rheumatology/Ragon Institute research group. The group is comprised of clinical investigators from the MGH Rheumatology Division and basic scientists from both the Ragon Institute and the Center for Inflammatory and Immunologic Disorders at MGH. We have described many of the clinical, pathological, and treatment characteristics of IgG4-RD and developed instruments to facilitate its study. We have also developed a detailed pathophysiological model and identified SLAM-F7 as a marker expressed on cells critical to IgG4-RD pathophysiology: a CD4+ cytotoxic T cell (CTL) and several types of B cells. We have phenotyped this CD4+CTL and the B cells with which it interacts, building a powerful case for the efficacy of an anti-SLAMF7 approach to treatment. Elotuzumab, approved in multiple myeloma, is a humanized monoclonal antibody that targets SLAM-F7. The Primary Clinical Project is a clinical trial program of elotuzumab in IgG4-RD, linked to robust mechanistic studies. Parallel with this work, we have led a worldwide trial of interleukin-6 receptor (IL6R) blockade in GCA that resulted in the worldwide approval of tocilizumab for that disease. Basic studies performed in our laboratories have demonstrated that GCA patients have an expanded population of inflammatory regulatory CD4+ T cells (Tregs) in their blood. These cells express markers of effector CD4+ T cells, produce IL-17, and carry a hypofunctional variant of the master regulatory factor Foxp3. The Alternate Clinical Project is a multi- center, two-arm, randomized, open-label clinical trial that will compare the efficacy and safety of IL-6 receptor blockade stepdown versus discontinuation in GCA. Patients will be followed longitudinally with careful clinical assessments to detect disease flares and capture clinical samples at the time of these events. We will investigate the roles of Tregs and other T cell subsets in both peripheral blood and at sites of disease. The Collaborative Project seek to ask three questions in building on previous work in human autoimmune fibrosis: Can immune dysregulation that drives autoimmunity be visualized at the site of its initiation, and can systems biology tools be utilized to quantitatively analyze this dysregulation? Can the entire gamut of immune cells in a tissue that is the target of autoimmunity be visualized, and immune cells interrogated visually in granular detail in order to map the relevant cell-cell interactions mapped? Can we use systems biology approaches in tissues to understand for fully the downstream mechanisms within the end organs affected by in autoimmune and fibrosis? Efforts in this proposed ACE program will be facilitated by: 1) a well-organized, highly-functional ACE Core; 2) the MGH Translational Medicine Group, an academic clinical research organization unique to MGH the ACE Funds Management Core; and, 3) the Ragon Institute biorepository as the ACE Core.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).